Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP-activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC-1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and deacetylation of PGC-1α, which was triggered by SIRT1/3.

The high incidence of cardiovascular disease and vitamin D deficiency in chronic kidney disease patients is well known. Vitamin D activation by omega-3 fatty acid (FA) supplementation may explain the cardioprotective effects exerted by omega-3 FA. We hypothesized that omega-3 FA and 25-hydroxyvitamin D (25(OH)D) supplementation may increase 1,25-dihydroxyvitamin D (1,25(OH)₂D) levels compared to 25(OH)D supplementation alone in hemodialysis (HD) patients that have insufficient or deficient 25(OH)D levels. We enrolled patients that were treated for at least six months with 25(OH)D < 30 ng/mL (NCT01596842). Patients were randomized to treatment for 12 weeks with cholecalciferol supplemented with omega-3 FA or a placebo. Levels of 25(OH)D and 1,25(OH)₂D were measured after 12 weeks. The erythrocyte membrane FA contents were also measured. Levels of 25(OH)D were increased in both groups at 12 weeks compared to baseline. The 1,25(OH)₂D levels at 12 weeks compared to baseline showed a tendency to increase in the omega-3 FA group. The oleic acid and monounsaturated FA content decreased, while the omega-3 index increased in the omega-3 FA group. Omega-3 FA supplementation may be partly associated with vitamin D activation, although increased 25(OH)D levels caused by short-term cholecalciferol supplementation were not associated with vitamin D activation in HD patients.

Fatty acids (FAs) are essential nutrients and main constituents of cell membranes that are involved in the signaling pathway and associated with health conditions. We investigated if blood or erythrocyte membrane FAs can predict the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and related complications. Omega-3 (n-3) FAs are important predictors for metabolic syndrome, diabetes, CVD, and CKD risks, and the n-3 index is also a good biomarker for sudden cardiac death in coronary artery disease. Linoleic acid, which is one of the major n-6 FAs reflecting recent dietary FA intake, may predict CVD risk and mortality in the general population and patients with CKD. Monounsaturated FAs (MUFAs) are also related to diabetes or diabetic nephropathy. Oleic acid, a major MUFA, is an emerging marker that is related to acute coronary syndrome, low glomerular filtration rate, and vascular calcification in patients with CKD, and can be modified by n-3 FA supplementation. Saturated FAs, trans-FAs, and FA desaturation/elongation are associated with CVD risk; however, few studies have been conducted on patients with CKD. In summary, blood or erythrocyte membrane FA measurements are important for CVD and CKD risk prediction and management. Further studies are needed to elucidate the FAs for their risk predictions.

Serum myostatin levels are increased according to renal function decline and myostatin may be a main mediator of chronic kidney disease-related sarcopenia. A previous study reported that serum myostatin level was negatively associated with abdominal aortic calcification (AAC) in older males. The aim of this study was to assess the association between serum myostatin level and AAC among dialysis patients of both sexes. In addition, we analyzed the relationship between serum myostatin level, muscle mass, and bone mineral density (BMD). In this cross-sectional study, we evaluated AAC in the lateral lumbar spine using plain radiography and BMD in 71 patients undergoing dialysis. We classified patients into two groups according to the median value of myostatin as follows: those with high myostatin levels (≥ 5.0 ng/mL) and those with low myostatin levels (< 5.0 ng/mL). The proportion of patients with an AAC score of five points or more was higher among those with low myostatin levels. Myostatin level was negatively associated with AAC scores on plain radiography and had a positive association with skeletal muscle mass and T-scores for BMD measured at the total hip and femur neck. Lower myostatin levels were independently associated with higher AAC scores following adjustment for age, sex, diabetes mellitus, dialysis vintage, dialysis modality, and osteoprotegerin level. Lower serum myostatin levels were associated with higher AAC scores, lower muscle mass, and lower BMD in dialysis patients. Further, prospective studies and those with larger cohorts are necessary to validate these findings.

Diabetic nephropathy is the leading cause of end-stage renal disease and is associated with an increased risk of cardiovascular events. Dietary omega-3 fatty acid (FA) has cardioprotective effect and is associated with a slower deterioration of albumin excretion in patients with diabetic nephropathy. In this study, we evaluated the effect of omega-3 FA on proteinuria in diabetic nephropathy patients who are controlling blood pressure (BP) with angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB). In addition, we identified changes in erythrocyte membrane FA contents. A total of 19 patients who were treated with ACEi or ARB for at least 6 months were treated for 12 weeks with omega-3 FA (Omacor, 3 g/day) or a control treatment (olive oil, 3 g/day). Proteinuria levels were unchanged after 12 weeks compared with baseline values in both groups. The erythrocyte membrane contents of omega-3 FA and eicosapentaenoic acid (EPA) were significantly increased, and oleic acid, arachidonic acid : EPA ratio, and omega-6 : omega-3 FA ratio were significantly decreased after 12 weeks compared with the baseline values in the omega-3 FA group. Although omega-3 FA did not appear to alter proteinuria, erythrocyte membrane FA contents, including oleic acid, were altered by omega-3 FA supplementation.

Serum myostatin and indoxyl sulfate (IS) levels increase with kidney function decline and may function as uremic toxins in chronic kidney disease (CKD)-related sarcopenia. Herein, we analyzed the association between serum myostatin and IS levels and sarcopenia in patients with CKD, by performing a post hoc analysis of baseline data extracted from the RECOVERY study (clinicaltrials.gov: NCT03788252) of 150 patients with CKD. We stratified patients into two groups according to the median value of myostatin (cutoff 4.5 ng/mL) and IS levels (cutoff 0.365 mg/dL). The proportion of patients with sarcopenia was higher in those with high IS levels but lower in those with high myostatin levels. The skeletal muscle mass index (SMI) and handgrip strength (HGS) were significantly lower in patients with high IS levels but significantly higher in patients with high myostatin levels. IS levels showed a negative correlation with glomerular filtration rate (GFR), SMI, and HGS. However, myostatin levels were positively correlated with SMI and HGS, but not with GFR. Sarcopenia was independently associated with age and IS level after adjustment. Increased levels of serum total IS might play a role in sarcopenia, while increased levels of serum myostatin are associated with muscle mass in patients with CKD.